Cycloamides of nitriloprostacyclins

ABSTRACT

This invention relates to certain structural and pharmacological analogs of prostacyclin (PGI 2 ) wherein a nitrogen atom is substituted for the 6,9α-epoxy-oxygen of prostacyclin. These novel nitrogen-containing prostacyclin-type compounds are useful for the pharmacological purposes for which prostacyclin is used, e.g., as antithrombotic agents, antihypertensive agents, antiasthma agents, nasal decongestants, or regulators of fertility and procreation.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of Ser. No. 807,514, filed June 17, 1977, now U.S. Pat. No. 4,097,489, issued June 27, 1978.

The present invention relates to prostacyclin analogs, the essential material constituting a disclosure thereof is incorporated here by reference from Ser. No. 807,514, filed June 17, 1977, now U.S. Pat. No. 4,097,489 issued June 27, 1978.

The present invention specifically relates to the following prostacyclin analogs:

(a) 9,11-Dideoxy-11α-hydroxymethyl-9α,6-nitrilo-PGF₁, piperidyl amide;

(b) 9,11-Dideoxy-9α,6-nitrilo-PGF₁, piperidyl amide;

(c) 9-Deoxy-9α,6-nitrilomethylene-PGF₁, piperidyl amide;

(d) 9-Deoxy-9α,5-nitrilo-PGF₁, piperidyl amide,

(e) (6R)- or (6S)-9-Deoxy-6,9α-imino-PGF₁, piperidyl amide;

(f) (6R)-N-methyl-6,9α-imino-PGF₁, piperidyl amide;

(g) (6R)-N-acetyl-6,9α-imino-PGF₁, piperidyl amide;

(h) (6S)-N-methyl-6,9α-imino-PGF₁, piperidyl amide;

(i) (6S)-N-methyl-6,9α-imino-PGF₁, piperidyl amide;

(j) 9-Deoxy-9α,6-nitrilo-cis-13-PGF₁, piperidyl amide;

(k) 9-Deoxy-9α,6-nitrilo-13,14-didehydro-PGF₁, piperidyl amide;

(l) 9-Deoxy-9α,6-nitrilo-14-chloro-PGF₁, piperidyl amide;

(m) 9-Deoxy-9α,6-nitrilo-13,14-dihydro-PGF₁, piperidyl amide;

(n) 2,2-Difluoro-9-deoxy-9α,6-nitrilo-15-methyl-PGF₁, piperidyl amide;

(o) Trans-2,3-didehydro-9-deoxy-9α,6-nitrilo-PGF₁, piperidyl amide;

(p) 9-Deoxy-9α,6-nitrilo-17-phenyl-18,19,20-trinor-PGF₁, piperidyl amide;

(q) 9-Deoxy-9α,6-nitrilo-16-phenoxy-17,18,19,20-tetranor-PGF₁, piperidyl amide;

(r) 9-Deoxy-9α,6-nitrilo-15-methyl-PGF₁, piperidyl amide;

(s) 9-Deoxy-9α,6-nitrilo-16,16-difluoro-PGF₁, piperidyl amide;

(t) 9-Deoxy-9α,6-nitrilo-16,16-dimethyl-PGF₁, piperidyl amide; and

(u) 9-Deoxy-9α,6-nitrilo-PGF₁, piperidyl amide. 

I claim:
 1. A prostacyclin analog of the formula ##STR1## wherein R₈ is hydrogen, hydroxy, or hydroxymethyl wherein Z₂ is ##STR2## wherein R₂ is alkyl of one to 4 carbon atoms, inclusive, or alkylcarbonyl of one to 4 carbon atoms, inclusive;wherein one of p, q, and r is the integer one and the other two are the integer zero; wherein Z₁ is(1) --(CH₂)_(g) --CH₂ --CH₂ --, (2) --(ch₂)_(g) --CH₂ --CF₂ --, or (3) trans--(CH₂)_(g) --CH═CH--,wherein g is the integer zero, one, or 2; wherein R₄ is hydrogen, hydroxy, or hydroxymethyl; wherein Y₁ is(1) trans--CH═CH--, (2) cis--CH═CH-- (3) --ch₂ ch₂ --, (4) trans--CH═C(Hal)--, or (5) --C.tbd.C-- wherein Hal is chloro or bromo; wherein M₁ is ##STR3## wherein R₅ is hydrogen or alkyl with one to 4 carbon atoms, inclusive wherein L₁ is ##STR4## a mixture of ##STR5## wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro; wherein L₄ is cycloamino selected from the group consisting of ##STR6## wherein R₂₁ and R₂₂ are (i) hydrogen;(ii) alkyl of one to 12 carbon atoms, inclusive; (iii) cycloalkyl of 3 to 10 carbon atoms, inclusive; (iv) aralkyl of 7 to 12 carbon atoms, inclusive; (v) phenyl; (vi) phenyl substituted with one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro; (vii) carboxyalkyl of one to four carbon atoms, inclusive; (viii) carbamoylalkyl of one to four carbon atoms, inclusive; (ix) cyanoalkyl of one to four carbon atoms, inclusive; (x) acetylalkyl of one to four carbon atoms, inclusive; (xi) benzoylalkyl of one to four carbon atoms, inclusive; (xii) benzoylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive; hydroxy, alkoxy of one to 3 carbon atoms, inclusive, carboxy, alkoxycarbonyl of one to four carbon atoms, inclusive, or nitro; (xiii) pyridyl; (xiv) pyridyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive; or alkoxy of one to 3 carbon atoms, inclusive; (xv) pyridylalkyl of one to 4 carbon atoms, inclusive; (xvi) pyridylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, alkoxy of one to 3 carbon atoms; (xvii) hydroxyalkyl of one to 4 carbon atoms, inclusive; (xviii) dihydroxyalkyl of one to 4 carbon atoms, and (xix) trihydroxyalkyl of one to 4 carbon atoms; with the further proviso that not more than one of R₂₁ and R₂₂ is other than hydrogen or alkyl; wherein R₇ is ##STR7## wherein m is the integer one to 5, inclusive, h is the integer zero to 3, inclusive; s is the integer zero, one, 2, or 3, and T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, or with the proviso that not more than two T's are other than alkyl; and the pharmacologically acceptable acid addition salts thereof when R₂ is not alkylcarbonyl.
 2. A prostacyclin analog according to claim 1, wherein R₈ is hydroxymethyl.
 3. 9,11-Dideoxy-11α-hydroxymethyl-9α,6-nitrilo-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 2. 4. A prostacyclin analog according to claim 1, wherein R₈ is hydrogen.
 5. 9,11-Dideoxy-9α,6-nitrilo-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 4. 6. A prostacyclin analog according to claim 1, wherein R₈ is hydroxy.
 7. A prostacyclin analog according to claim 6, wherein p is one.
 8. 9-Deoxy-9α,6-nitrilomethylene-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 7. 9. A prostacyclin analog according to claim 6, wherein q is one.
 10. 9-Deoxy-9α,5-nitrilo-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 9. 11. A prostacyclin analog according to claim 6, wherein r is one.
 12. A prostacyclin analog according to claim 11, wherein Z₂ is ##STR8##
 13. (6R)- or (6S)-9-Deoxy-6,9α-imino-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 12. 14. A prostacyclin analog according to claim 11, wherein Z₂ is ##STR9##
 15. (6R)-N-methyl-6,9α-imino-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 14. 16. (6R)-N-acetyl-6,9α-imino-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 14. 17. (6S)-N-methyl-6,9α-imino-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 14. 18. (6S)-N-acetyl-6,9α-imino-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 14. 19. A prostacyclin analog according to claim 11, wherein Z₂ is ##STR10##
 20. A prostacyclin analog according to claim 19, wherein Y₁ is cis--CH═CH--.
 21. 9-Deoxy-9α,6-nitrilo-cis-13-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 20. 22. A prostacyclin analog according to claim 19, wherein Y₁ is --C.tbd.C--.
 23. 9-Deoxy-9α,6-nitrilo-13,14-didehydro-PGF₁,piperidyl amide, a prostacyclin analog according to claim
 22. 24. A prostacyclin analog according to claim 19, wherein Y₁ is trans--CH═C(Hal)--.
 25. 9-Deoxy-9α,6-nitrilo-14-chloro-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 24. 26. A prostacyclin analog according to claim 19, wherein Y₁ is --CH₂ CH₂ --.
 27. 9-Deoxy-9α,6-nitrilo-13,14-dihydro-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 26. 28. A prostacyclin analog according to claim 19, wherein Y₁ is trans--CH═CH--.
 29. A prostacyclin analog according to claim 28, wherein Z₁ is --(CH₂)_(g) --CH₂ --CF₂.
 30. 2,2-Difluoro-9-deoxy-9α,6-nitrilo-15-methyl-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 29. 31. A prostacyclin analog according to claim 28, wherein Z₁ is trans--(CH₂)_(g) --CH═CH--.
 32. Trans--2,3--didehydro-9-deoxy-9α,6-nitrilo-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 31. 33. A prostacyclin analog according to claim 28, wherein Z₁ is --(CH₂)_(g) --CH₂ --CH₂ --.
 34. A prostacyclin analog according to claim 33, wherein g is zero.
 35. A prostacyclin analog according to claim 34, wherein R₇ is ##STR11##
 36. 9-Deoxy-9α,6-nitrilo-17-phenyl-18,19,20-trinor-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 35. 37. A prostacyclin analog according to claim 34, wherein R₇ is ##STR12##
 38. 9-Deoxy-9α,6-nitrilo-16-phenoxy-17,18,19,20-tetranor-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 37. 39. A prostacyclin analog according to claim 34, wherein R₇ is --(CH₂)_(m) --CH₃ --.
 40. A prostacyclin analog according to claim 39, wherein m is
 3. 41. A prostacyclin analog according to claim 40, wherein R₅ is methyl.
 42. 9-Deoxy-9α,6-nitrilo-15-methyl-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 41. 43. A prostacyclin analog according to claim 40, wherein R₅ is hydrogen.
 44. A prostacyclin analog according to claim 43, wherein at least one of R₃ and R₄ is fluoro.
 45. 9-Deoxy-9α,6-nitrilo-16,16-difluoro-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 44. 46. A prostacyclin analog according to claim 43, wherein at least one of R₃ and R₄ is methyl.
 47. 9-Deoxy-9α,6-nitrilo-16,16-dimethyl-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 46. 48. A prostacyclin analog according to claim 43, wherein R₃ and R₄ are both hydrogen.
 49. 9-Deoxy-9α,6-nitrilo-PGF₁, piperidyl amide, a prostacyclin analog according to claim
 48. 